Problematic End Points in a Keratinocyte Carcinoma Chemoprevention Trial—Reply

In Reply We appreciate the close scrutiny of our published work and the opportunity to elaborate on the end points we used for analysis of the trial data. The VAKCC Trial primary end point was the rate of occurrence of keratinocyte carcinoma (KC) over the course of the 4-year trial. In the process of creating and executing this trial, however, the study team explicitly discussed that there were other important outcomes. In particular, while we did not have evidence to guide our estimation of the timing and duration of the effect of our intervention, if any, on the occurrence of KC, basal cell carcinoma, or squamous cell carcinoma (SCC), we realized that a short-term effect on risk (eg, during the first year) could be of considerable clinical importance even if the effect did not persist for the entire duration of the trial. We further recognized that even if there was a substantial effect in the first year, it could be lost in the 4-year results unless specifically examined. Hence, when analysis plans were discussed prior to unblinding the data, it was explicitly stated by the study chair, and summarized in the form of email guidance to the study statistician, that outcomes at 1 year were important to calculate and report. With the focus on completing the report, we chose not to officially amend the statistical analysis plan. This was an administrative decision that did not prevent appropriate analysis and should not prevent appropriate scientific interpretation. The final analyses, as reported, revealed a clinically and statistically significant 75% reduction in SCC risk in the first year. It is appropriate for this finding to influence the clinical care of those at high risk of face and ear SCC.